Disease genes discovered through linkage analysis in familial Parkinson disease (PD) are yielding new insights into the pathogenesis of this neurodegenerative disorder. However, the known genes explain only a minor portion of all PD, and the chromosomal regions linked to other families are large and contain numerous genes. The discovery of additional hereditary causes of PD may help further elucidate the underlying etiopathogenesis and provide new pharmacological targets. It is therefore crucial that additional families are characterized. In an extended Amish family in northeastern Ohio, clinical information for familial Parkinsonism has been obtained. To test the hypothesis that genetic influences contribute to the expression of Parkinsonism in this Amish pedigree, the immediate aims of this project are three-fold: 1) to fully ascertain the disease phenotype of the affected individuals, through genealogical data, clinical history, medical records, and neurological exam, 2) to identify the genetic locus or loci associated with the disease phenotype, initially by evaluating previously identified genetic loci, and conducting a genome-wide scan using conventional linkage analysis, transcript mapping, and gene identification, and 3) to perform candidate gone analysis to test whether specific gene modifiers enhance or suppress the expression of the disease phenotype. The candidate's long-term goals are to apply well-established and emerging methods toward understanding the genetic basis of Parkinsonism. This grant will help the candidate establish an independent career in academic neurology with specialization in movement disorders and neurogenetics by allowing the candidate 1) to evaluate and treat patients in a movement disorders clinic under the guidance of Thomas L. Davis, M.D., and 2) to learn the laboratory, statistical, and computational methods of genetic epidemiology. This will be accomplished through conduct of the proposed research project and participation in formal courses under the guidance of the candidate's mentor, Jonathan L. Haines, Ph.D.